We propose to assess whether the risk of Parkinson's disease (PD) among veterans of the Vietnam War is predicted by exposure to herbicides, lower cholesterol, diabetes, higher body mass index (BMI), and use of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors), non-steroidal anti-inflammatory drugs (NSAIDs), and anti-hypertensive medications. If particular medications reduce the risk of PD, then they could potentially be considered as a prophylactic treatment against PD among veterans known or suspected to be at higher risk of PD. The proposed investigation will take advantage of access to a population of an estimated 3.2 million Vietnam veterans. This population is uniquely suited to address the question of the specific involvement of herbicides in PD because of their wide exposure to herbicides at levels much higher than in any other population in which this question has been studied, and the existence of a sophisticated exposure assessment model based on troop location information. In addition, the detailed medical and pharmacy records in a population as large as that of Vietnam veterans will allow for some of the strongest, least biased results to date on the role of several different medical conditions and medications, while providing sufficient power to explore dose-response relations and other subanalyses. We will identify PD cases and controls through VA medical records and randomly select 700 cases and 1,400 controls. Hypothesis 1: Higher exposure to Agent Orange and other herbicides is associated with increased risk of PD. Hypothesis 2A: Higher cholesterol levels are associated with a decreased risk of PD. Hypotheses 2B: Diabetes is associated with an increased risk of PD. Hypothesis 2C: Higher BMI is associated with an increased risk of PD. Hypothesis 3A: Statin use is associated with a decreased risk of PD. Hypothesis 3B: NSAID use is associated with a decreased risk of PD. Hypothesis 3C: Calcium channel blocker use is associated with a decreased risk of PD. As an exploratory aim, we will also examine possible effect modification of the herbicide-PD association by the medical conditions and medication use variables examined in Hypotheses #2 and #3, as well as by smoking. In light of the very high levels of herbicide exposure among Vietnam veterans and the frequency of the risk conditions of hypotheses 2A-2C among this population, understanding the relation of such exposures to a debilitating illness such as PD is highly relevant to the VA mission of caring for our combat veterans. Furthermore, if it can be shown that any of the medications we will examine reduce risk of PD or modifies risk attributable to herbicide exposure, then these medications could potentially be considered as a prophylactic treatment against PD among veterans known or suspected to have been exposed to herbicides. PUBLIC HEALTH RELEVANCE: Previous research has suggested that exposure to herbicides may be a risk factor for the development of Parkinson's Disease (PD). It has also been suggested that lower levels of serum cholesterol, higher body mass index, and diabetes are also risk factors for PD. In contrast, use of the "statin" class of lipid-lowering agents, non-steroidal anti-inflammatory drugs (NSAIDs), and anti-hypertensive medications may protect against the development of PD. Overall, however, the evidence remains somewhat equivocal for all these factors. This project will bring some of the strongest data to date to examine all of these possible associations. Because many combat veterans were heavily exposed to herbicides during the Vietnam War, have the possible higher risk medical conditions we are examining, but could also potentially reduce their risk of PD by using the medications we will study, this research is very relevant to veteran's health.